Two spontaneous null mutations in the mouse Sharpin gene (Sharpincpdm and Sharpincpdm-Dem) result in the chronic proliferative dermatitis mouse (Locus symbol: cpdm) phenotype which appears to be a homologue of human idiopathic hypereosinophilic syndromes. SHARPIN is critical in the development and function of the immune system, and also plays an important role in cell proliferation, differentiation, apoptosis, and cancer through the NFKB, integrin, and Toll-like receptor (TLR) signaling networks. Our overall hypothesis is that SHARPIN functions in multiple overlapping biochemical pathways resulting in a complex phenotype upon loss of function. By unraveling the pathogenesis of the disease in skin and other organ systems and confirming the human homologue, we will identify novel and better methods for the diagnosis and treatment of patients. Our new conditional Sharpin null mouse (B6(Cg)-Tyrc-2J Sharpintm1Sun/Sun) provides a novel tool to investigate, with great precision, the role of this recently discovered gene in the NFKB, integrin, and TLR signaling networks. Loss of SHARPIN results in different patterns of network activation based on cell type. To define how each cell type responds, we will selectively inactivate Sharpin in keratinocytes, fibroblasts, endothelial cells, adipose tissue, various subsets of lymphocytes, etc. using cell-specific promoters driving cre-recombinase. Concurrently, we will inactivate specific points in the three major gene networks under investigation by creating compound mutants with our Sharpin null mice of conditional nulls. These approaches will define the key cell types involved in the pathogenesis of this hypereosinophilic syndrome and dissect how Sharpin functions within three major signaling networks. A prominent feature of the cpdm phenotype is chronic dermatitis with many eosinophils and overexpression of type 2 cytokines along with a diminished systemic type 1 immune response. Dendritic cells play a pivotal role in directing the type of immune and inflammatory responses. We will address the mechanism underlying the chronic type 2 inflammation through selective deletion of Sharpin in dendritic cells and deletion of specific cytokine genes. A complementary approach builds on our observation that loss of Sharpin in different inbred strains had a dramatic effect on severity of disease indicating strain specific major modifying genes were involved. We will validate a recently identified major candidate gene. In addition, by using quantitative trait locus mapping and gene association studies, we will identify other genes that regulate this phenotype, most likely those involved in regulating NFKB, integrin, and TLR signaling networks. Lastly, we will utilize several de-identified human blood/DNA repositories to screen human patients with hypereosinophilic syndromes to determine which of these human diseases our chronic proliferative dermatitis mutant mice most closely resemble.